Project description:Genome-wide mRNA expression profiles of 70 primary gastric tumors from the Australian patient cohort. Like many cancers, gastric adenocarcinomas (gastric cancers) show considerable heterogeneity between patients. Thus, there is intense interest in using gene expression profiles to discover subtypes of gastric cancers with particular biological properties or therapeutic vulnerabilities. Identification of such subtypes could generate insights into the mechanisms of cancer progression or lay the foundation for personalized treatments. Here we report a robust gene-xpression-based clustering of a large collection of gastric adenocarcinomas from Singaporean patients [GSE34942 and GSE15459]. We developed and validated a classifier for the three subtypes in Australian patient cohort. Profiling of 70 primary gastric tumors on Affymetrix GeneChip Human Genome U133 Plus 2.0 Array. All tumors were collected with approvals from Peter MacCallum Cancer Center, Australia; the Research Ethics Review Committee; and signed patient informed consent.
Project description:Genome-wide mRNA expression profiles of 70 primary gastric tumors from the Australian patient cohort. Like many cancers, gastric adenocarcinomas (gastric cancers) show considerable heterogeneity between patients. Thus, there is intense interest in using gene expression profiles to discover subtypes of gastric cancers with particular biological properties or therapeutic vulnerabilities. Identification of such subtypes could generate insights into the mechanisms of cancer progression or lay the foundation for personalized treatments. Here we report a robust gene-xpression-based clustering of a large collection of gastric adenocarcinomas from Singaporean patients [GSE34942 and GSE15459]. We developed and validated a classifier for the three subtypes in Australian patient cohort.
Project description:Genome wide mRNA expression profiling of 94 gastric tumours derived from Australian based cohort was performed. . From this data we identified a cluster of co-expressed genes termed the stromal response cluster which almost perfectly differentiates tumor from its non-malignant gastric tissue and hence can be regarded as a highly tumor-specific gene expression signature. We show that these genes are consistently co-expressed across a range of independent gastric datasets as well as other cancer types suggesting a conserved functional role in cancer. Profiling of 94 primary gastric tumors on Affymetrix GeneChip Human Genome U133 Plus 2.0 Arrays. All tumors were collected with approvals from Peter MacCallum Cancer Center, Australia; the Research Ethics Review Committee; and signed informed patient consent.
Project description:Genome wide mRNA expression profiling of 94 gastric tumours derived from Australian based cohort was performed. . From this data we identified a cluster of co-expressed genes termed the stromal response cluster which almost perfectly differentiates tumor from its non-malignant gastric tissue and hence can be regarded as a highly tumor-specific gene expression signature. We show that these genes are consistently co-expressed across a range of independent gastric datasets as well as other cancer types suggesting a conserved functional role in cancer.
Project description:This SuperSeries is composed of the following subset Series:; GSE15455: GEMINI (Gastric Encyclopedia of Molecular Interactions and Nodes for Intervention) Phases A-C; GSE15456: Primary Gastric Cancer Expression Profiles (UK Patient Cohort); GSE15459: Gastric Cancer Project '08 (Singapore Patient Cohort); GSE15537: GEMINI (Gastric Encyclopedia of Molecular Interactions and Nodes for Intervention) Phases A-C, normal skin fibroblasts Experiment Overall Design: Refer to individual Series
Project description:Kynureninase is a member of a large family of catalytically diverse but structurally homologous pyridoxal 5'-phosphate (PLP) dependent enzymes known as the aspartate aminotransferase superfamily or alpha-family. The Homo sapiens and other eukaryotic constitutive kynureninases preferentially catalyze the hydrolytic cleavage of 3-hydroxy-l-kynurenine to produce 3-hydroxyanthranilate and l-alanine, while l-kynurenine is the substrate of many prokaryotic inducible kynureninases. The human enzyme was cloned with an N-terminal hexahistidine tag, expressed, and purified from a bacterial expression system using Ni metal ion affinity chromatography. Kinetic characterization of the recombinant enzyme reveals classic Michaelis-Menten behavior, with a Km of 28.3 +/- 1.9 microM and a specific activity of 1.75 micromol min-1 mg-1 for 3-hydroxy-dl-kynurenine. Crystals of recombinant kynureninase that diffracted to 2.0 A were obtained, and the atomic structure of the PLP-bound holoenzyme was determined by molecular replacement using the Pseudomonas fluorescens kynureninase structure (PDB entry 1qz9) as the phasing model. A structural superposition with the P. fluorescens kynureninase revealed that these two structures resemble the "open" and "closed" conformations of aspartate aminotransferase. The comparison illustrates the dynamic nature of these proteins' small domains and reveals a role for Arg-434 similar to its role in other AAT alpha-family members. Docking of 3-hydroxy-l-kynurenine into the human kynureninase active site suggests that Asn-333 and His-102 are involved in substrate binding and molecular discrimination between inducible and constitutive kynureninase substrates.